Nourbakhsh et al. have the honour of publishing the first article of 2021 that will change my practice. As bright and shiny as all the monoclonal antibodies on our treatment shelf are compared to the dusty and lacklustre drugs used to treat the symptoms of MS. However, the symptomatic treatments determine day-to-day life for many pwMS: fatigue, spasms, neuropathic pain, etc.
For fatigue, the most frequently prescribed drug is amantadine. This drug seems to be a “Jack-of-all-trades”. In 1963, it was discovered because of its antiviral properties in treating people infected by the influenza virus. In 1969, the mythical duo Schwab and England discovered its soothing effect on tremor and dyskinesias in people with Parkinson’s disease. In 1974, Shapira tested whether there was an effect of amantadine in pwMS and that appeared to be fatigue reduction. The underlying hypothesis: MS is potentially caused by a viral infection (speaking of off-target). Other drugs that we use to treat fatigue: modafinil (mode of action unknown) and methylphenidate (especially in the US, also used to treat ADHD).
The effect of these compounds on fatigue has been explored in several publications over the past decades. However, the majority of these trials were characterised by significant flaws. It is important to be aware of three important facts before reading anything around this topic:
- Amantadine, modafinil and methylphenidate are adverse-effect prone drugs. If you compare them 1:1 or in a cross-over trial (e.g. in which pwMS first take 4 wks the active drug and afterwards 4 wks placebo) to placebo, there is no such thing as blinding.
- Placebo reduces the scores of the Modified Fatigue Impact Scale (MFIS) (ranging from 0 (no fatigue) to 84 (a lot of fatigue)) with on average 10 points.
- Statistical significance does not equal clinical relevance. The minimal important difference on the MFIS is lies between 4 and 8 points, even if lower differences between placebo and drugs generate a significant P-value.
Does anybody see the link between these two pictures?
Solution: Although it’s tempting to focus in these COVID-19-times on the Italian variant (where you can sip from Aperol spritz), the link between both of these pictures is the fact that it’s a Latin square. The mathematical significance of a Latin square is an n x n array filled with n different symbols, each occurring exactly once in each row and exactly once in each column.
And this is the exact concept that Nourbakhsh et al. applied in their fatigue study:
- Amantadine 6wks – Nothing 2wks – Placebo 6 wks – Nothing 2 wks – Modafinil 6 wks – Nothing 2 wks – Methylphenidate 6 wks
- Placebo 6 wks – Nothing 2wks – Methylphenidate 6 wks – Nothing 2 wks – Amantadine 6 wks – Nothing 2 wks – Modafinil 6 wks
- Modafinil 6 wks – Nothing 2 wks – Amantadine 6 wks – Nothing 2 wks – Methylphenidate 6 wks- Nothing 2 wks – Placebo 6 wks
- Methylphenidate 6 wks – Nothing 2 wks – Modafinil 6 wks – Nothing 2 wks – Placebo 6 wks – Nothing 2 wks – Amantadine 6 wks
This means that pwMS were subjected to 4 different sequences of treatment while being blinded for the actual treatments. At week 5 of each treatment cycle, pwMS had to fill out the MFIS.
The beauty of this design is that the confounding effect of placebo becomes significantly less relevant. People are exposed to four treatment cycles with the same drugs and have essentially no clue anymore when they would be on an active component and when not. The results of the study are very clear: none of the drugs exerted a significant effect on the MSIF. Hence, none of them reduced fatigue in pwMS. The MSIF even increased with 0.7 points when using amantadine and there were marginal reductions in MSIF for methylphenidate (2.0 points) and modafinil (1.6 points). Of note, the active drugs caused about double the number of moderate adverse effects compared to placebo.
This contrasts with data on the effect of exercising in MS. A Cochrane review of 2015 found that various type of exercise therapy reduce fatigue with 6.9 points on the MSIF. Exercise therapy was interpreted very liberally. One of the schemes incorporated the Nintendo Wii Balance board that trains your balance while snowboarding in the French Alps. Moreover, programming consistently more exercise is a healthy habit with no side effects (unless you overdo it :-)). However, motivating pwMS for daily or frequent exercise is unfortunately much more difficult than prescribing a tablet. Both pwMS and health care practitioners plead guilty of being complacent on this matter. Brainstorming with pwMS on how to be more active, even when having a disability, is much more time-consuming and requires much more out-of-the-box thinking than prescribing an extra tablet for the dosset box. I accept the challenge after reading this article. What about you?
Bardia Nourbakhsh, Nisha Revirajan, Bridget Morris, Christian Cordano, Jennifer Creasman, Michael Manguinao, Kristen Krysko, Alice Rutatangwa, Caroline Auvray, Salman Aljarallah, Chengshi Jin, Ellen Mowry, Charles McCulloch, Emmanuelle Waubant
Background: Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.
Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.
Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).
Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.